http://tinyurl.com/3xekt

Phase I trial of UFT/leucovorin and irinotecan in patients with
advanced cancer.

Veronese ML, Stevenson JP, Sun W, Redlinger M, Algazy K, Giantonio B,
Hahn S, Vaughn D, Thorn C, Whitehead AS, Haller DG, O'Dwyer PJ.

Abramson Cancer Center, University of Pennsylvania 51 N 39th St, MAB-
103, Philadelphia, PA 19104, USA.

UFT (BMS-200604, Uftoral(R)) is an oral fluoropyrimidine that
combines uracil and the 5-fluorouracil (5-FU) prodrug, ftorafur, in a
4:1 molar ratio with single-agent activity in breast and
gastrointestinal cancers. In vitro studies have shown that irinotecan
downregulates thymidylate synthase (TS) expression in tumour cells,
leading to synergy between irinotecan and 5-FU that is maximal when
irinotecan is given 24 h prior to 5-FU. Given this observed synergy
and the confirmatory clinical activity of combination therapy with 5-
FU, leucovorin (LV) and irinotecan, we performed a phase I trial to
determine the maximum tolerated doses (MTD) of UFT, LV, and
irinotecan. Treatment consisted of irinotecan administered as a 90-
min intravenous (i.v.) infusion on day 1 followed by twice daily oral
UFT/LV on days 2-15, repeated every 21 days. Initial doses were
irinotecan 200 mg/m(2) and UFT 200 mg/m(2)/day, with LV dose fixed at
60 mg/day. 31 patients received a total of 130 cycles of UFT/LV and
irinotecan. 3 of 9 patients experienced grade 3/4 diarrhoea at the
highest dose level of irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day.
Other toxicities included neutropenia, anaemia, alopecia,
nausea/vomiting and fatigue. Further dose escalation was not pursued
since this level of toxicity was appropriate for future phase II
study. One patient with colorectal cancer experienced a partial
response and 9 patients with non-small cell lung, colorectal and
gastro-oesophageal junction carcinomas had disease stabilisation
lasting 4-26 (median 6) cycles. Methylenetetrahydrofolate reductase
(MTHFR) C677T genotype was analysed in peripheral mononuclear cells
(PMNs) obtained from 24 patients. 2 patients had the homozygous TT
polymorphism and 1 of them had grade 3 diarrhoea at the first dose
level. Irinotecan on day 1 followed by a 14-day course of oral UFT/LV
beginning on day 2 is well tolerated, and suitable for testing in
several tumour types. Doses recommended for further study on this
schedule are irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day, with LV
60 mg/day.

PMID: 14962716 [PubMed - in process]

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